Volume 28 Issue 4 Article 10

2020

Gold nanoparticle-based colorimetric and electrochemical sensors for the detection of illegal additives

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Recommended Citation Li, Li; Zhang, Ming; and Chen, Wei (2020) "Gold nanoparticle-based colorimetric and electrochemical sensors for the detection of illegal food additives," Journal of Food and Drug Analysis: Vol. 28 : Iss. 4 , Article 10. Available at: https://doi.org/10.38212/2224-6614.3114

This Review Article is brought to you for free and open access by Journal of Food and Drug Analysis. It has been accepted for inclusion in Journal of Food and Drug Analysis by an authorized editor of Journal of Food and Drug Analysis. Gold nanoparticle-based colorimetric and

electrochemical sensors for the detection of illegal REVIEW ARTICLE food additives

Li Li a,*,1, Ming Zhang a,1, Wei Chen b,**

a Kangda College, Nanjing Medical University, Lianyungang, 222000, PR China b Department of Pharmaceutical Analysis, Fujian Medical University, Fuzhou, 350004, PR China

Abstract

Lately, scandals associated with the illegal addition of poisonous chemicals to food for commercial interests have been gradually disclosed to the public. Problems related to do not only harm public health but also affect the stability of economic and social development. Food safety has become a common issue in society, and strengthening the related regulations have become increasingly important. Although conventional techniques are accurate and sensitive in the detection of the vast majority of illegal food additives, they rely on time-consuming, labor-intensive procedures that depend on expensive instruments. Thus, efficient and rapid identification of poisonous, illegal additives in food is a crucial task in analytical chemistry. Recently, in this context, gold nanoparticles (GNPs) have attracted considerable attention because of their optical, electronic, catalytic, and chemical properties. Their excellent properties have facilitated the widespread use of GNPs in different sensors. This review covers the two most common GNP-based sensors with colorimetric and electrochemical responses, which have proven to be effective in the detection of illegal additives. The GNP-based sensors comply with the requirement of modern analysis, such as high selectivity, sensitivity, simplicity, rapidity, and portability. Thus, they have great potential as powerful sensing tools for food safety screening. This review elucidates the utility and advances of GNP-based colorimetric and electrochemical sensors for the detection of illegal additives in the and in the supervision of and safety. Additionally, an outlook of the trends and future development of research on these sensors is provided.

Keywords: Gold nanoparticles, Illegal additives, Colorimetric sensors, Electrochemical sensors, Quick detection

1. Introduction they pose to human health [3]. However, some illegal additives are still added to food, and this ood safety is a major global concern because has become one of the most prominent food F of an increased public awareness of health safety issues. Incidents caused by illegal additives and quality standards [1]. Food additives are in food have occurred recurrently, threatening natural or synthetic substances that are widely public health and leading to a social distrust of used in modern food industry during processing, the food industry and loss of public confidence in packaging, and transport. They can improve the the regulatory system [4,5]. For instance, the quality, durability, and stability of food products following substances have been reported as and adjust their color, smell, and flavor [2]. Illegal illegal food additives: , nitrite, mel- food additives are non-edible substances that are amine, sodium formaldehyde sulfoxylate, alum, prohibited in human food because of the threat beef extract, clenbuterol, sulfur dioxide, Sudan

Received 6 February 2020; revised 20 April 2020; accepted 29 July 2020. Available online 1 December 2020

* Corresponding author at: Kangda College, Nanjing Medical University, Lianyungang, 222000, PR China.

** Corresponding author at: Department of Pharmaceutical Analysis, Fujian Medical University, Fuzhou, 350004, PR China. E-mail addresses: [email protected] (L. Li), [email protected] (W. Chen). 1 Authors contribute equally to this article.

https://doi.org/10.38212/2224-6614.3114 2224-6614/© 2020 Taiwan Food and Drug Administration. This is an open access article under the CC-BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 642 JOURNAL OF FOOD AND DRUG ANALYSIS 2020;28:641e653 EIWARTICLE REVIEW

red, diethylhexyl phthalate (DEHP), fluorescent catalytic properties, which are appealing to optimize bleacher, and talcum powder [5]. Because of the the sensitivity of electrochemical sensors by ampli- frequent food safety incidents, strengthening the fying the electrode surface, enhancing the electron food quality and safety regulation has become transfer between electroactive species and the electrode, and catalyzing electrochemical reactions topical [6,7]. Accordingly, the development of [11]. In general, GNPs are used in electrochemical methods to identify poisonous and illegal addi- sensors as assisting components. Functionalized tives in food products are urgently required to GNPs may act as both signal transducer and mo- minimize the public health hazards. lecular receptor in a sensing platform, simplifying Recently, nanotechnology has emerged as a the design of the latter and enhancing its sensitivity. promising field of research in preventing food safety Sometimes, GNPs can act as electro-catalysts, issues. With its rapid development, novel methods especially for the redox reaction [10]. GNP-based for detecting illegal food additives have been found. colorimetric sensors are simple and rapid, and Among the nanomaterials, gold nanoparticles GNP-based electrochemical sensors have high (GNPs) have attracted considerable attention in sensitivity and selectivity, simultaneously being food safety because of their unique, size-dependent facile, robust, and easy to use. Thus, in food safety properties, such as their optical, electric, catalytic, and quality assessment, these two kinds of sensors and magnetic behaviors, and because of their have been widely applied in rapid, real-time and biocompatibility, ease of chemical modification, and on-site monitoring and detection of illegal food ad- dispersibility in water [8,9]. These properties make ditives. This review presents a brief overview of the GNPs very promising for producing novel sensors common applications and recent advances of GNP- for application in food safety control [10]. In based colorimetric and electrochemical sensors for colloidal solutions, GNPs can exhibit different op- detecting illegal food additives. tical properties, according to their dispersed or Because of the outbreak of publications in this aggregated state. When the interparticle distance is field, we can not mention all the published reports approximately lower than the average GNP diam- and rather choose to discuss and summarize those eter, the color of the solution changes from red to that are most representative. Thus, the recent blue, corresponding to a band shift of the surface development of GNP-based colorimetric and elec- plasmon from 523 nm to 610e670 nm that can be trochemical sensors for detecting illegal food addi- easily observed by simple naked-eye observation or tives and their applications in the last five years spectroscopic measurements. Thus, they have been (2015e2019) are explained in detail (see Fig. 1 and used as simple colorimetric sensors for the quick Fig. 2). Future prospects and challenges are also detection of illegal additives in food samples. discussed briefly. Other applications of GNP-based Furthermore, GNPs have excellent conductivity and sensors such as fluorescent sensors,

Fig. 1. Systematic representation of application of GNP-based colorimetric and electrochemical sensors to detect illegal additives in food. JOURNAL OF FOOD AND DRUG ANALYSIS 2020;28:641e653 643

especially in babies and small pets [15,16]. Recently, has represented a widespread concern in food safety. Therefore, effective, reliable, and highly sensitive methods for detecting melamine in food products with the sensitivity required by regulatory REVIEW ARTICLE authorities are urgently needed. In this context, GNP-based colorimetric and electrochemical sensors have become powerful Fig. 2. Systematic representation of application of GNP-based colori- detection tools for identifying melamine in food metric and electrochemical sensors to detect illegal additives in food. products. Evolution of the number of publications concerning the keywords ‘‘gold ”þ“ ”þ“ ” ‘‘ nanoparticles colorimetric sensors additives and gold nano- 2.1.1. GNP-based colorimetric sensors for melamine particles”þ“electrochemical sensors”þ“additives” on indexed journals between 2015 and 2019. The insert pie graph exhibits the percentage of detection the available scientific reports which concerned the GNP-based sensors Our group used bare GNPs as a colorimetric using colorimetric and electrochemical techniques from 2015 to 2019. probe for melamine detection [17]. Because of the The data comes from the research on ‘‘web of science”. strong attraction between the amine groups of = melamine and surface-bound AuCl4 AuCl2 ions, melamine can directly induce the aggregation of immunosensors, and optical-based biosensors are bare GNPs, resulting in an obvious color change not discussed. from wine red to blue. However, colorimetric methods for melamine detection by naked GNPs 2. GNP-based colorimetric and require tedious sample preparation processes or electrochemical sensors of illegal food complicated operation procedures, which are additives disadvantageous for on-site detection [18]. More- over, bare GNPs are unstable in colloidal solution Common illegal additives include melamine, and can undergo aggregation due to -induced Sudan dyes, b-agonists in food of animal origin, and screening, resulting in false detection events [19]. To nitrite. For the detection of these poisonous chem- stabilize GNPs in aqueous media and improve the icals, different GNP-based colorimetric and elec- sensitivity of the GNP-based colorimetric assay, trochemical sensors have been developed. modified GNPs have been developed to detect melamine. Ligand-modified GNPs are characterized 2.1. Melamine detection by high steric and hydration-based interparticle repulsion. Thus, they can modify the aggregation of As an important nitrogen-heterocyclic industrial GNPs in an oriented and controlled manner, and raw material, melamine (1,3,5-triazine-2,4,6-tri- are more stable in high ionic strength conditions amine), a trimer of cyanamide with a 1,3,5-triazine than bare GNPs [20,21]. skeleton, is widely used in industry for the pro- Because environmental factors such as the pH duction of, e.g., plastics, amino resins, and flame value, ionic strength, and temperature might influ- retardants [12,13]. Melamine is not approved for ence the aggregation of GNPs, some new strategies application in or food additives. have also been reported for the detection of mel- However, because of its high nitrogen content (66% amine. For example, Xin's group has developed a of its mass) and low cost, melamine has been ille- series of colorimetric sensors to detect melamine gally introduced by unethical manufacturers in in- during the synthesis of GNPs [22]. Detailed mech- fant milk, wheat gluten, and pet food to inflate the anistic investigations indicate that melamine in- apparent content of crude proteins [14]. In fact, terrupts the process of synthesis of GNPs and traditional protein detection methods, such as the stimulates the aggregation of formed GNPs (see Kjeldahl and Dumas methods, determine the ni- Fig. 3(c)). trogen content without identifying its source. Thus, the presence of melamine can falsely increase the 2.1.2. GNP-based electrochemical sensors for protein concentration. Unfortunately, melamine it- melamine detection self has acute toxicity and can gradually form Recently, several reports described the successful insoluble reticulate crystals in the kidneys with its use of GNPs in hybrid-modified electrodes for the hydrolysate (cyanuric acid). A long-term and electrochemical detection of melamine. For excessive intake of melamine-tainted food can cause instance, Chen et al. have developed a sensor based urinary calculus, renal dysfunction, and even death, on a glassy carbon electrode (GCE) modified by 644 JOURNAL OF FOOD AND DRUG ANALYSIS 2020;28:641e653 EIWARTICLE REVIEW

Cancer, Sudan dyes are strictly banned as food ad- ditives by both the and the European Union [26]. However, because of their fascinating red color and low cost, they are illegally used as food additives by many unscrupulous manufacturers to improve the appearance of food products such as chili powders, beverages, sweets, palm oil-based products, frozen meat, etc. [27]. Therefore, for public health protection, monitoring the presence of Sudan dyes in food products is highly important, and the development of sensitive analytical methods to detect them is urgently required.

2.2.1. GNP-based electrochemical sensors for Sudan dye detection Modified electrode systems have become research focus in electrochemical sensing because of their efficiency and accuracy [28]. For the electrochemical detection of Sudan dyes, the modifier is a key factor that can highly influence the sensitivity and selec- tivity of the detection [29]. GNPs are known to be efficient labels and viable materials to modify the surface of electrodes, thereby enhancing the detec- Fig. 3. GNP-based colorimetric sensors for the detection of melamine tion limit of electrochemical sensors [30]. Thomas and nitrite. (a) Bare GNP-based colorimetric sensors for the detection of et al. have developed an electrochemical sensor fi melamine. (b) Modi ed GNP -based colorimetric sensors for the based on the catalytic activity of the GNPs deposited detection of melamine (or nitrite). (c) Sensing principle for melamine analysis during the synthesis of GNPs. on a GCE to detect Sudan I in chili powder and ketchup samples. The GNPs displayed excellent electrocatalytic activity in the oxidation of Sudan I GNP/reduced graphene oxide (RGO) nano- [31]. The sensor exhibited two distinct linear composites with a high melamine sensitivity [23]. In response ranges of 4.0 10 5e1 10 3 mol/L and this electrochemical sensing system, RGO provides 2 10 5e7 10 7 mol/L. The lower detection limit a platform for the uniform distribution of GNPs and of the sensor was 1.0 10 8 mol/L (Table 1). enhances the electron transfer rate, improving the To date, many electrochemical sensors prepared sensitivity of the sensor. For melamine measure- by GNPs combined with other functional materials ment, hexacyanoferrate was used as electrochemical for detecting Sudan dyes have been reported. For reporter. Melamine can be grafted on the surface of example, an electrochemical sensor based on a GNPs by the interaction between the amino groups molecularly imprinted polymer entrapped by dou- e of melamine and GNPs via Au N bond, which ble-stranded DNA (ds-DNA) and gold nanoparticles leads to the suppression of the peak current of has been reported to detect Sudan II in chili and hexacyanoferrate because of the poor electro- ketchup sauce [32]. The imprinted polymer pro- chemical activity of melamine. The suppression vided great specific molecular recognition and high degree is related with the concentration of mel- stability in harsh chemical and physical conditions amine and can be used for the quantitative [33]. In these kinds of polymers, molecular recog- determination. nition relies on the intermolecular interaction, such as hydrogen, p-p, or ionic bonds and electrostatic, 2.2. Sudan dyes detection hydrophobic, dipole, or van der Waals interactions, between the functional monomers and the template Sudan dyes (comprising Sudan I, II, III, and IV) [34]. The ds-DNA and GNPs enhance the selectivity are a family of lipophilic azo dyes that are widely and sensitivity of the measurement. In particular, used in the chemical industry, and especially as the introduction of GNPs in molecularly imprinted coloring agents in , oil, petrol, , and shoe polymers has been reported to increase the elec- fi polish [24,25]. Because they are classi ed as carcin- trode specific area, enhance the electron transfer ogens by the International Agency for Research on between the recognition sites and the Table 1. Typical applications of gold nanoparticle-based colorimetric and electrochemical sensors for the detection of illegal food additives. Sample source Biosensors Nanomaterials Concentration Detection limit Pretreatment to real samples Ref. range infant formula melamine colorimetric bare GNPs 5.0 10 6 ‒ 2.0 10 7 g/L precipitate proteins by [17] 2.0 10 4 g/L trichloroacetic solution, then collect the supernatant milk melamine colorimetric 1,4-dithiothreitol 8.0 10 8 ‒ 2.4 10 8 M dilute 1000 times with distilled water [19] modified GNPs 6.0 10 7 M; 6.0 10 7 ‒ 1.5 10 6 M processed raw milk melamine colorimetric asymmetrically 1.05 10 3 1.05 10 3 mmol/L precipitate proteins with 10% [21] PEGylated GNPs e1.00 103 mmol/L trichloroacetic acid and acetonitrile, then sonicate, centrifuge, and filtrate 7 7 liquid milk melamine colorimetric methanobactin- 3.90 10 2.38 10 mol/L precipitate proteins with 10% [22] 2020;28:641 ANALYSIS DRUG AND FOOD OF JOURNAL mediated synthesis e3.97 10 6 mol/L trichloroacetic acid, then shake, of GNPs centrifuge, and filtrate food contact materials melamine electrochemical GNPs/RGO/GCE 5e50 nmol/L 1.0 nmol/L immerse in food simulants (water or [23] (plate or fruit tray) 3% acetic acid) then heat and filtrate ketchup and chilly Sudan I electrochemical GNPs/GCE 4.0 10 5 1.0 10 8 mol/L ultrasonic extraction with ethanol [31] sauce e1 10 3 ;2 10 5 and filtrate e7 10 7 mol/L chili and ketchup Sudan II electrochemical treated 1.0e20.0; 20.0 0.3 nmol/L ultrasonic extraction with ethanol [32] sauce pencilgraphite e500.0 nmol/L and filtrate electrode with DNA, o- phenylenediamine, and GNP bioimprinted polymer chilli powder and Sudan I electrochemical GNPs/RGO/GCE 0.01e70 mmol/L 1 nmol/L ultrasonic extraction with ethanol [37] ketchup sauce and filtrate chopped red chili, Sudan I electrochemical ILRGO@GNPs/ 1.0 10 10 5.0 10 11 mol/L for chopped red chili and tomato [39] e 6 e tomato sauce; the GCE 1.0 10 mol/L sauce, ultrasonic extraction with 653 apple juice and grape ethanol and filtrate; for the apple juice juice and grape juice, use directly without pretreatment beef ractopamine colorimetric ApteGNPs 0e400 ng/mL 10 ng/g homogenize with acetate [56] ammonium buffer (pH ¼ 5.2), then enzymatically digest, centrifuge and filtrate pork clenbuterol electrochemical MoS2eAu-PEI- 0.01e2 mg/mL 0.00192 mg/mL homogenize with 0.1 M HClO4 [57] hemin/GCE solution, then sonicate and centrifuge meat products nitrite colorimetric/fluorescent/ GNRs-Azo-GNPs 0.5e100 mmol/L 0.05 mmol/L cut into 1 cm disk and 2 2cm [65] including ham sausage SERS triple sensing square piece and red-braised pork sausages nitrite colorimetric Janus PEGylated 10.8e174 mmol/L 10.8 mmol/L shred, then dissolve with a saturated [66] 645 GNP probe boric acid solution (continued on next page)

REVIEW ARTICLE 646 JOURNAL OF FOOD AND DRUG ANALYSIS 2020;28:641e653 EIWARTICLE REVIEW ] ] ] ] ] ] electrochemical transducer, and act as catalysts that 68 72 73 69 70 76 [ [ [ [ [ [ amplify the electrochemical reactions [35]. Addi- tionally, GNP/RGO composites have proven to be good electrode materials in electrochemical sensing, ltrate fi because electrodes modified using these composites esh to cut

ltrate again exhibited highly improved electrocatalytic activity fl fi

ltrate and electrochemical stability [36]. For instance, a fi GNP‒decorated RGO electrochemical sensor of high performance has been developed for the detection of Sudan I in chili powder and ketchup sauce [37]. Compared with the reported analogs, the solution, centrifuge and 4 HCl (pH 7, 0.5 M) and GNP/RGO hybrid electrode displayed increased e ltrate, centrifuge and ltrate ush with ultrapure water, then electrocatalytic activity in the oxidation of Sudan I heat, cool to roomfi temperature, heat, precipitate proteins withZnSO 30% vortex and centrifuge methanol supplemented with NaCl, then vortex and centrifuge fi into small pieces, homogenizeTris with fl squeeze into juice, ultrasonic treatment, heat and because of the excellent catalysis and charge trans- fer ability of GNPs. Furthermore, the incorporation of ionic liquids into GNP/RGO-based electro- chemical sensors can significantly improve their sensitivity, retaining their chemical stability and mol/L homogenize, then ultrasonication, mol/L mol/L shred, add saturated borax solution, m m g/mL precipitate proteins using ice-cold

m high catalytic activity [38]. Wang et al. reported m GNP/RGO composites functionalized by an ionic Detection limit Pretreatment to real samples Ref. liquid of 1-allyl-3-methylimidazolium chloride for the electrochemical detection of Sudan I in chopped red chili, tomato sauce, apple juice, and grape juice. Such fabricated Sudan I sensor reveals a wide linear mol/L 0.13 g/mL 92 mol/L 0.25 m m m range from 1.0 10 10e1.0 10 6 mol/L, low 10 ppm 0.1 ppm thawed, then select the 11 50 mg/L 2.6 900 150 mmol/L 20 mmol/L precipitate proteins with methanol, e detection limit of 5.0 10 mol/L, high selectivity 6000 e 1000 e e e e range 0.5 0.01 5 and long-term stability [39].

2.3. Detection of b-agonists in food of animal origin aptamer 20

-ATP- b ed gold -agonists are a group of phenylethanolamine e p fi compounds with different substituents of the aro- modi electrode [EMIM][Otf]/CHIT/ GCE nanocomposites matic rings or aliphatic amino groups and include mainly clenbuterol (CLE), ractopamine (RAC), sal- butamol (SAL), terbutaline, cimaterol, phenyl- ethanolamine A (PEA) [40,41]. They are used in the clinical treatment of pulmonary diseases such as asthma [42,43] and chronic obstructive pulmonary disease [44]. Additionally, they can promote protein synthesis, increase muscular growth, and decrease b the deposition of fats in livestock by stimulating 2- colorimetric bare GNPsadrenergic 92 receptors [45,46]. However, in livestock fed with b-agonists, the residues can stay in the tissues for a long time [47,48]. When people consume products of such livestock, acute poisoning nitrite electrochemical ERGO/GNPs/SPCE 1 detergents can result, with symptoms such as muscular tremor or pain, cardiac palpitation, nervousness, headache, dizziness, nausea, vomiting, fever, chills, etc. [49]. Therefore, b-agonists have been banned as growth promoters for livestock in most countries, including the European Union and China [50‒52]. Neverthe- less, in some regions, b-agonists have been illegally used as food additives in feeding livestock for eco- sh formalin electrochemicalfi FDH/GNPs/ packaged drinking water, processed meats and aquatic products Table 1. (continued) Sample source Adulterant Biosensors Nanomaterials Concentration sausage nitrite electrochemical GNP/ milkfi anionic pickled radish nitrite electrochemical GNPs/GO-SH milk ureanomic colorimetric pro t. GNPs To provide food safety to the JOURNAL OF FOOD AND DRUG ANALYSIS 2020;28:641e653 647

consumer, such illegal food additives must be very low concentrations [62,63]. Furthermore, ni- strictly monitored. However, the wide variety of b- trite can interfere with the oxygen transport system agonists and their extensive use in farming repre- and may result in methaemoglobinaemia, which sent an overwhelming challenge for governments, can cause tissue hypoxia and, possibly, death requiring daily supervision and routine monitoring. [59,63]. The World Health Organization has REVIEW ARTICLE included nitrite in its list of [64]. 2.3.1. GNP-based colorimetric sensors for the detection Consequently, the nitrite levels in food samples are of b-agonists in food of animal origin globally strictly limited to protect public health. Aptamers (Apts), which are single-stranded oli- Because of the serious hazard to health and the gonucleotides exhibiting excellent biological recog- frequent occurrence of food safety accidents related nition capability, can be used as recognition to nitrite, this is currently severely restricted or components in the design of biosensors and banned as a food additive in many countries [5,64]. analytical applications [53‒55]. Wang et al. reported However, to save costs, it is still used indiscrimin- a sensitive visual detection method for the identifi- ately to replace allowed additives in the food pro- cation of ractopamine (RAC) in beef using cessing industry. Therefore, the detection of nitrite ApteGNPs aptasensor [56]. The concentration of in food is of great importance, especially for food RAC could be quantified visually or using a UVeVis quality control. spectrometer in the wide range from 10 to 400 ng/ With the continuous development of technologies mL. The detection limit is as low as 10 ng/mL. in analytical chemistry, the methods for detecting nitrite in food are increasingly diverse, and new 2.3.2. GNP-based electrochemical sensors for the methods are emerging. Rapid, cost-effective detection of b-agonists in food of animal origin methods for on-site detection of nitrite in food Yang et al. developed an electrochemical non- products are becoming increasingly common e enzyme sensor by fabricating layered MoS2 Au- because of their easy test protocols and instanta- PEI-hemin nanocomposites-modified GCE for neous results. In this context, many researchers detecting CLE in real pork samples [57]. Because of have attempted to develop novel sensors for the the unique physical and electrical properties corre- detection of nitrite. lated with its two-dimensional structure and high surface area, the MoS2 nanosheet is very interesting 2.4.1. GNP-based colorimetric sensors for the detection as supporting material for hierarchical composites of nitrite in electrochemical systems [58]. The electrochemical Li et al. developed the Griess reaction-based sensor proposed in Ref. [57] combined the advan- paper strips for colorimetric/fluorescent/surface tages of the MoS2 nanosheet, the high conductivity enhanced Raman scattering (SERS) triple-mode of GNPs, the presence of polyethyleneimine (PEI) sensing of nitrite in meat products [65]. The triple- amino-groups, and the electrochemical catalytic mode sensor was based on hybrid gold nanorods- activity of hemin, exhibiting excellent detection azo-GNPs (GNRs-Azo-GNPs) assemblies, which performance to CLE. Such sensor reveals a wide can not only be used as a naked-eye detector of linear ranging from 10 ng/mL to 2 mg/mL, low nitrite, because of the color change from orange- detection limit of 1.92 ng/mL CLE, favorable yellow to purple upon addition of nitrite, but also as reproducibility and stability. a highly selective fluorescence-quenching probe. Additionally, it can be used as a SERS substrate for 2.4. Detection of nitrite reliable quantitative analysis of nitrite. Thus, the triple-mode sensor can be used as a paper-based Sodium nitrite is an industrial salt commonly test strip for on-site, fast screening of nitrite with a known as nitrite. It is a pale yellow, granular crystal high sensitivity and selectivity. or powder, with a shape very similar to salt [59]. In Xiong et al. developed a Janus-type polyethylene the food processing industry, nitrite is used to glycol-based (PEGylated) GNP probe for colori- improve the appearance (color), flavor, and texture metric detection of nitrite in sausages with a sur- of processed meat [60]. Additionally, it can be used prisingly high analytical performance [66]. The as a food for meat or meat products PEGs and recognition ligands (e.g., 4-amino- because it inhibits the growth of clostridium botu- benzenethiol, 4-ABT) were asymmetrically func- linum spores [61]. However, it has proven to be a tionalized on the surface of GNPs to form a GNP- threat to human health. In fact, nitrite is an based probe. In this probe, the biocompatible and essential precursor of carcinogenic N-nitrosamines, water-soluble PEGs were used to maintain the which can result in serious health issues even at colloidal stability of GNPs against extreme 648 JOURNAL OF FOOD AND DRUG ANALYSIS 2020;28:641e653 EIWARTICLE REVIEW

conditions in real samples [67], whereas 4-ABT was assure food safety and avoid health risks to con- used as a ligand for sensing nitrite. With this design, sumers, novel analytical procedures have been pro- the probes showed high colloidal stability, signal posed for the detection of these illegal additives. robustness, specificity, and sufficient sensitivity in Kumar et al. developed an easy-to-use, non-enzy- the detection of nitrite in different complex samples. matic, dual readout aptasensor with both colorimetric and fluorescence sensing functions to detect urea 2.4.2. GNP-based electrochemical sensors for the adulteration in milk [72]. The urea aptasensor uses detection of nitrite bare GNPs to transduce the signal of aptamer binding Recently, different kinds of nitrite sensors have to urea in simultaneous intrinsic fluorescence and been fabricated by chemically modifying the elec- color change. Kumar et al. developed a simple trodes to improve their performance. For example, method for the detection of anionic detergents (ADs, Jian et al. developed a screen-printed carbon elec- mainly consist of linear alkylbenzenesulfonate and trode (SPCE) modified with a composite of electro- have been widely used as surfactants) in milk using chemically reduced graphene oxide (ERGO) and bare GNPs as colorimetric sensing platforms based GNPs for an effective electrocatalytic analysis of ni- on aggregation and dispersion of the GNPs [73]. trite in several complex food samples, including packaged drinking water, processed meats, and 2.5.2. GNP-based electrochemical sensors for the aquatic products [68]. The optimized electrode detection of other illegal additives exhibited excellent electroactive and electrocatalytic Formaldehyde is classified as a by the properties for the detection of nitrite, including a low International Agency for Research on Cancer (IARC) oxidation potential (0.65 V), wide linear range [74], and is prohibited as a food additive in China and (1e6000 mM), high sensitivity (0.3048 mA mM 1 cm 2), the European Union [5,75]. However, formaldehyde is low detection limit of 0.13 mM (S/N ¼ 3), and great sometimes used illegally as a food preservative in selectivity. aquatic products. Recently, Aini et al. developed an Üzer et al. developed an electrochemical sensor electrochemical biosensor using a GCE modified with with a GNP/p-aminothiophenol ( p-ATP)-modified formaldehyde dehydrogenase (FDH)/GNPs/1-ethyl- gold electrode to detect nitrite in sausage samples 3-methylimidazolium trifluoromethanesulfonate [69]. The GNP/PATP nanocomposites can form an ([EMIM][Otf])/chitosan (CHIT) to detect formalin in electrocatalytic layer on the surface of the modified fish samples [76]. The linear working range for the gold electrode, decreasing the overpotential and quantitation of formaldehyde was 0.01e10 ppm with a enabling faster electron-transfer kinetics for nitrite detection limit of 0.1 ppm. oxidation. Under the optimum conditions, the linear range for the detection of nitrite was 0.5e50 mg/L 3. The sensing mechanisms with a detection limit of 0.12 mg/L. Pan et al. developed a GCE modified by a GNPs/ 3.1. The sensing mechanisms of GNP-based colorimetric sensors L-cysteine functionalized graphene oxide (GNPs/ GO-SH) nanocomposite for the electrochemical The sensing mechanisms of GNP-based colori- detection of nitrite in pickled radish [70]. Because of metric sensors for the detection of illegal additives the low stability of GO, it is essential to improve the can be divided into two types: aggregation principle stability of this sensor and functionalize it by chemical modification. The surface of GO was and anti-aggregation principle. modified using the sulfhydryl group of L-cysteine to improve the electrical conductivity of the electrode 3.1.1. Aggregation principle The localized surface plasmon resonance (LSPR) and the GNP loading [64,70]. As a result, the sensi- is one of the most remarkable features of GNPs [77]. tivity and selectivity of this electrochemical sensor A consequence of this unique optical property, an- was enhanced. alyte-induced aggregation of GNPs in aqueous media is accompanied with a color change, which 2.5. Detection of other illegal food additives has been employed for the colorimetric detection of illegal additives [78,79]. Currently, many studies 2.5.1. GNP-based colorimetric sensors for the detection have reported illegal additives detection in food of other illegal additives products using naked or modified GNPs as colori- Recently, the economically motivated adulteration metric sensors, which can be easily observed either of milk and infant formula using hazardous chemicals by naked eye or simple spectroscopy measurements like melamine, formalin, hydrogen peroxide, di- (see Fig. 3(a) and (b)). chromate, urea, and detergents has increased [71]. To JOURNAL OF FOOD AND DRUG ANALYSIS 2020;28:641e653 649

In addition, GNPs can readily interact with bio- attachment of GNPs and adsorption of abundant molecules, yielding improved signal amplification nitrite, promoting rapid and heterogeneous electron and targeted recognition. GNPs can adsorb small transfer [68]. Apts by taking advantage of electrostatic attraction, The sensing mechanism of the electrochemical hydrophobic absorption, and covalent bonding. The biosensor using FDH/GNPs/[EMIM][Otf]/CHIT REVIEW ARTICLE aptamer-conjugated GNPs (ApteGNPs) is a prom- modified GCE to detect formalin in fish samples is ising tool for on-site detection in bioanalysis [80,81]. as follows [76]: FDH acts as the electron transfer to The mechanism of ApteGNPs for the detection of facilitate the addition of one hydrogen atom to þ illegal additives is shown in Fig. 4. In the absence of NAD and reduced it to NADH, whereas formal- illegal additives, the Apt binds to GNPs, preventing dehyde converted to formic acid. CHIT has been salt-induced aggregation of the GNPs. If illegal ad- used for the effective immobilization of molecules ditives is present, it selectively binds to the Apt, through electrostatic attraction in order to improve leaving the GNPs uncoated. This results in salt- the stability and deposited onto the GCE. GNPs induced aggregation of the GNPs along with a red- increased the surface area of immobilization. to-blue color change. Meanwhile, the ionic liquid [EMIM][Otf] acts as an ionic which diffuses easily due to its wide 3.1.2. Anti-aggregation principle solubility in the solutions, especially during elec- Addition of inducer (NaCl) to the GNPs neutral- trochemical measurements. Combining all of the izes their surface charge and causes aggregation characteristic above, FDH/GNPs/[EMIM][Otf]/ which is reflected in color change of the solution CHIT indicated great potential in electrochemical from red to purple. However, upon addition of activity for formaldehyde detection. illegal additives (such as ADs) with optimized NaCl concentration in GNPs solution, the solution color 4. Conclusion and future perspectives remains red, due to inhibitory effect on GNPs ag- gregation (Fig. 5). In Fig. 5, in the presence of ADs, With the globalization of the food market, food safety issues have attracted great attention. As the negatively charged ADs can neutralize the þ illegal additives are one of the main food safety is- charge of sodium ions (Na ) of the NaCl, thus sues, it is vital to develop simple, sensitive, and inhibiting the aggregation of GNPs induced by the universal monitoring strategies of these additives to NaCl. ensure the quality and safety of food. Because of their excellent optical, electronic, 3.2. The sensing mechanism of GNP-based catalytic, and chemical properties, GNPs have electrochemical sensors great potential in the development of colorimetric and electrochemical sensing technologies. This re- GNPs have outstanding electrical conductivity, view has provided a brief overview of representa- high surface area, and electrochemical activity that tive GNP-based colorimetric and electrochemical make them promising for electrochemical sensing sensors for the detection of illegal additives in the [9]. Modifying the electrode of electrochemical food industry. Some typical applications of GNP- sensors with GNPs and other functional materials based colorimetric and electrochemical sensors for can increase the electrochemically active surface, the detection of illegal food additives are briefly and exhibit strong biocompatibility, high electrical conductivity, and excellent catalytic activity [9,82‒ shown in Table 1. These techniques provide effective platforms for simpler, more rapid, cost- 84]. For example, the mechanism for the electro- effective, and practical analysis of illegal additives catalytic oxidation of nitrite at the ERGO/GNPs/ compared to traditional analytical methods. How- SPCE is expected as below [68]: because of the large ‒ ever, these technologies are still emerging and surface area of ERGO nanosheets, NO is firstly 2 facing several challenges. Firstly, colorimetric absorbed onto the ERGO surface to form a complex 0 methods are intuitive, practical, simple and rapid, of ½Au =ERGOðNO Þ. Then the neighboring Au is 2 þ but require highly specific experimental condi- electrochemically oxidized to Au and nitrogen di- oxide (NO ) is formed via the electron transferred tions. Food products are multicomponent complex 2 systems. some food sample matrices may be through the conductive graphene network. Imme- ‒ capable of interacting with gold nanoparticle, diately, NO2 is further oxidized to NO3 in the þ easily resulting in the aggregation of GNPs. Such presence of strongly active Au . The GNPs were non-specific reactions lead to a false positive used as efficient electrocatalysts for the oxidation of result, seriously affecting the precision of mea- nitrite [69,85], and the winkled ERGO sheets pro- surements. After modifying GNPs with specific vided a three-dimensional scaffold for the 650 JOURNAL OF FOOD AND DRUG ANALYSIS 2020;28:641e653 EIWARTICLE REVIEW

Fig. 5. Sensing principle for ADs analysis based on anti-aggregation of Fig. 4. Schematic representation of aptamereGNPs based methods for GNPs. the detection of RAC and urea. (a) Without RAC (or urea). (b) With fi RAC (or urea). then ltered. Solid complex samples such as meat usually need to be homogenized, then digested in ligands such as biocompatible polymers, anti- a suitable solution, followed by centrifugation, bodies, functional small molecules, nucleic acids, dilution and/or filtration (Table 1). For the rapid peptide, and proteins, a highly selective for various and sensitive on-site quantitative detection of the analytes in complex food products may be ach- analytes in complex matrix samples, portable pre- ieved. Secondly, the introduction of recognition treatment systems will be the future trend of moieties on the surface of GNPs, can enhance the development. Finally, along with the incessant selectivity of target analytes. But sometimes insta- research on the application of GNPs and other bility of the modified GNPs frequently occur. Fine nanomaterials, several potential risks and toxicity tuning the functionalization strategies could be the issues associated with the application of these solution to introduce these recognition moieties on nanomaterials on environment and human health the GNPs without sacrificing their stability. have been revealed [86,87], and should also be Thirdly, driven by economic interests, numerous considered. illegal additives may coexist in foodstuff. The simultaneous detection of different kinds of ana- Funding lytes is a new trend, but the colorimetric sensors based on GNPs are currently limited in this field. This study was funded by the Natural Science Electrochemical sensors can potentially be used to Foundation for Colleges and Universities of monitor different analytes simultaneously, there- Jiangsu Province (Grant No. 17KJD150005), the & fore they are expected to be subject to further Jiangsu Overseas Research Training Program for & developments to this end. Fourthly, the electro- University Prominent Young Middle-aged chemical sensors suffer from the need for signifi- Teachers and Presidents Fund, the Qing Lan cant electroactivity of the analyte and the poor Project Fund of Jiangsu Province, Science and repeatability due to electrode fouling and charging. Technology Project Fund of Gaoxin District in So there is an increasing demand for building up a Lianyungang (Grant No. HZ201906), the Fifth complementary multi-mode sensing methods Phase of 521 Project Fund of Lianyungang, the within one system because they can offer more Petrel Plan Project Fund of Lianyungang, and than one kind of output signal simultaneously, Science and Technology Funds of Kangda College thus making the detection results more convincing. of Nanjing Medical University (Grant No. Fifthly, both sensors usually need complicated KD2016GCCRCYJ01, KD2016GCCRCYJ02, KD201 sample pretreatment procedure to avoid matrix 8KYJJYB001 and KD2018KYJJYB010). interference. Only few liquid samples such as the apple juice and grape juice were used directly Declaration of competing interest without pretreatment. For most liquid samples fl such as milk, are usually treated as the following: There is no potential con ict of interest to declare. precipitate proteins, then remove the precipitate by centrifugation, and at last, filter the superna- References tant. Solid complex samples such as chili powder or ketchup sauce are usually extracted with the [1] Ye YL, Guo HY, Sun XL. Recent progress on cell-based biosensors for analysis of food safety and quality control. solvent ethanol and the ultrasonic extractor, and Biosens Bioelectron 2019;126:389e404. JOURNAL OF FOOD AND DRUG ANALYSIS 2020;28:641e653 651

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